Project Summary Foodborne disease is an important health threat and an immense economic burden worldwide. One important category of causative agents of foodborne diseases is attaching and effacing (A/E) pathogens, which include human pathogens enteropathogenic Escherichia coli (EPEC), enterohemorrhagic E. coli (EHEC) and their murine equivalent Citrobacter rodentium (CR). A/E pathogens share most of their genes and pathogenic mechanisms to subvert host signaling pathways and immune responses. Particularly, increasing number of studies demonstrate that A/E pathogen infections cause more severe morbidity and mortality in immunocompromised hosts. However, the critical host-pathogen interactions in the gut and the mechanism(s) through which A/E pathogens suppress host immune responses have not been fully understood, especially under immunocompromised condition. Our recent studies demonstrate that a novel site-specific DNA recombinase (Ssr) plays a crucial role in CR infection-caused severe morbidity and mortality in immunocompromised animals. This project aims to elucidate the pathogenic role of Ssr in CR infection- induced pathogenesis in immunocompromised hosts and the relevance of Ssr in human A/E pathogens. Thus, we will assess the impact of Ssr on colonic inflammatory response and epithelial integrity during A/E pathogen infections in Aim 1 and elucidate the molecular mechanism(s) through which Ssr affects virulence gene expression during A/E pathogen infections in Aim 2. At the conclusion of these studies, we will provide novel insights into the complex foodborne pathogenesis whereby A/E pathogen virulence is elegantly regulated during infections. It will also advance our understanding of the sophisticated pathogen-host interactions that may lead to novel strategies for prevention and treatment of A/E pathogen infections and foodborne diseases, especially under immunocompromised conditions.